The proposed epidemiologic research is based on our prior 24-year achievements in the development of unique populations and our stored serum and lymphocyte libraries. These resources will be used to search for environmental triggers that initiate beta cell destruction or precipitate clinical diabetes. We will use cutting edge T lymphocyte technology in order to identify presumably viral precipitators of autoimmunity and factors that may accelerate the prediabetes process to clinical disease. We will seek to differentiate those with high-risk HLA alleles who progress rapidly to total destruction of insulin producing beta cells, from those who have an indolent autoimmune course or present with clinical diabetes without the usual multiple autoantibodies. The hypotheses to be tested are: 1) a typical T-cell Vbeta bias is associated with enteroviral infection and with the autoimmune progression of prediabetes. 2) T-cell autoimmunity is precipitated by environmental triggers and precedes the appearance of autoantibodies. Increasing numbers of T-cell responses and autoantibodies are markers of progressive prediabetes. 3) Insulin resistance is a diabetes accelerator in subjects with slowly progressive autoimmunity. 4) There are less T- and B-cell antigen spreading and more insulin resistance in LADAs compared to rapid progressors. Slow progressors have more insulin resistance than rapid progressors. Data derived from this research will give clues regarding the environmental pathogenesis of T1D and identify the initial autoimmune abnormalities in high-risk first-degree relatives. These will assist in the design of intervention strategies in future studies. This research will also form the basis for other potential substudies of the T lymphocyte characteristics that are different in very young and older T1D children.